Theiler's murine encephalomyelitis virus (TMEV) produces a chronic infection in its natural host, characterized by the presence of extensive inflammatory demyelination in the spinal cord. Demyelination occurs in well demarcated plaques and is characterized by relapses and remissions making this one of the best models for human multiple sclerosis (M.S.). Several studies suggest that demyelination in this model is immune mediated and genetically controlled by at least two genes, one associated with and the other outside of the major histocompatibility complex (MHC). Although there is general agreement on the immune character of the pathogenesis of myelin destruction in this model, the mechanisms responsible for myelin injury are still controversial. With this proposal we shall address several important questions: 1) the genetic susceptibility of different strains and recombinant-inbred strains to the disease; 2) the role that cell infiltrates may play in the production of pathological lesions. In particular, we shall try to identify different cell phenotypes in white matter lesions including hematogenous and/or CNS cells expressing Ia antigen. We shall quantify by flow cytometry different types of inflammatory cells after isolation from CNS and shall try to determine their antigenic specificity by limiting dilution. We shall study the effect that selective depletion of specific immune cell populations may have in the clinical and pathological expression of the disease; 3) we shall study the effects that immunosuppression and reconstitution may have in both the acute and chronic phases of the disease; 4) we shall continue our studies on the role that an EAE-like mechanism of anti-myelin attack may have in infected animals. We shall try to identify the possible presence of cells against myelin antigens by repetitive alternating cycles of antigen stimulation and IL-2 expansion and will try to transfer disease in naive animals if such cells are elicited. also we shall investigate whether myelin is able to tolerize animals before infection; 5) since DTH response to TMEV appears to be the best parameter to differentiate susceptible versus non-susceptible animals, we shall explore the possible role that an anti-virus immune response may have on myelin injury by by-stander effect; 6) since a possible mechanism of myelin injury could be through an immunological attack on oligodendrocytes expressing viral antigens on their surface membrane, we shall try to identify such antigens in vivo and in vitro by immunocytochemistry.